Bipolar Type U (BP U) disorder affects 1.5-2.5 percent of the U.S. adult population and results in annual healthcare costs of about $20 billion. BP II disorder is characterized by a high recurrence of major depressive episodes (MDE) and is associated with substantial morbidity and mortality. The recognition of effective treatments for recurrent MDE is of critical importance. Unfortunately, relatively little attention has been given to its treatment. Concern over a "manic switch" during treatments of BP U MDE have impeded the development of effective antidepressive treatments and relapse prevention therapies for this illness. We have recently published pilot data demonstrating that fluoxetine may be a safe and effective monotherapy for the treatment of BP U MDE and for relapse-prevention treatment of BP II MDE. We propose to determine whether fluoxetine monotherapy is an effective treatment for both the initial and relapse-prevention treatment of BP II MDE. We will also determine whether fluoxetine monotherapy is associated with a low incidence of manic and hypomanic switch episodes in these patients. To answer these questions, 184 BP II patients will be recruited over 4 years from the Depression Research Unit (DRU)-which screens 400-500 new patients per year (of which about 25 percent meet DSM-IV criteria for BP II or NOS disorder). Patients will be treated initially with fluoxetine for 10 weeks and patients who remit from their MDE will be randomized, in a double-blind fashion, to receive one of the following relapse-prevention treatments for one year: i) fluoxetine monotherapy (20mg/daily) ii) lithium monotherapy (600-1200mg/daily) iii) the combination of lithium (600-1200mg/daily) and fluoxetine (20mg/daily), or iv) placebo. We believe that our study has the potential to have a significant impact upon current clinical practice in the appropriate management of bipolar depressed patients; an extremely important public-health matter.